: The goals of the PI's research program are to define mechanisms of peripheral tolerance induction in order to develop new clinical strategies in transplantation. This application is a competing renewal to continue studies initiated to determine the mechanisms of action of co stimulatory blockade. Among the foundations of this application is the observation that there is major heterogeneity in the response of a uniformly activated population of T cells in that up to 40 percent of stimulated cells fail to proliferate following activation by antigen or anti-CD3. A large number of activated cells die during the course of the response, however both proliferating and non-proliferating cells can survive. Whether those that survive are the cells that mediate late immune responses is not known. These findings lead the PI to propose a model in which T cells reacting to alloantigen traverse a series of decision nodes leading to proliferation, survival or death, effector function, and memory. The cumulative decisions at these branch points determine the outcome of immune response. The PI proposes to characterize and define specific events in the life span of T cells, focusing on parameters that dictate an individual cell's choice. The PI will use the ability to track cells labeled with CFSE, together with adoptive transfer and identifiable TCR transgenic T cells to study the fate and function of T cells during alloantigen- and peptide antigen-specific responses. Aim 1 will define signal transduction in T cells that fail to proliferate following encounter with antigen and determine if these cells are regulatory. Aim 2 will determine if cells that do proliferate are the source of the memory cell pool or regulatory cells. Aim 3 will investigate the hypothesis that direct allorecognition leads to rapid expansion of T cells followed by AICD versus survival of T cells using the indirect allorecognition pathway that are postulated to lead to chronic rejection. The PI proposes that these studies will provide novel insights into the mechanisms of immunologic tolerance and assist in the development of new strategies to achieve this goal in the clinical setting.